Pub Date : 2024-05-31eCollection Date: 2024-01-01DOI: 10.1177/17588359241242959
Diego Teyssonneau, Charles Dariane, Eric Barret, Jean-Baptiste Beauval, Laurent Brureau, Gaëlle Fiard, Gaëlle Fromont, Gilles Créhange, Mathieu Gauthé, Alain Ruffion, Raphaële Renard-Penna, Romain Mathieu, Paul Sargos, Morgan Rouprêt, Guillaume Ploussard, Guilhem Roubaud
Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.
{"title":"PARP inhibitors in prostate cancers, is it time for combinations?","authors":"Diego Teyssonneau, Charles Dariane, Eric Barret, Jean-Baptiste Beauval, Laurent Brureau, Gaëlle Fiard, Gaëlle Fromont, Gilles Créhange, Mathieu Gauthé, Alain Ruffion, Raphaële Renard-Penna, Romain Mathieu, Paul Sargos, Morgan Rouprêt, Guillaume Ploussard, Guilhem Roubaud","doi":"10.1177/17588359241242959","DOIUrl":"10.1177/17588359241242959","url":null,"abstract":"<p><p>Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular <i>BRCA2</i>. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared.
Methods: We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models.
Results: Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY versus AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%).
Conclusion: Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.
{"title":"First-line treatments for advanced non-squamous non-small cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a systematic review, network meta-analysis, and cost-effectiveness analysis.","authors":"Wentao Tian, Lishui Niu, Yin Shi, Shuishi Li, Rongrong Zhou","doi":"10.1177/17588359241255613","DOIUrl":"10.1177/17588359241255613","url":null,"abstract":"<p><strong>Introduction: </strong>The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared.</p><p><strong>Methods: </strong>We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models.</p><p><strong>Results: </strong>Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY <i>versus</i> AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%).</p><p><strong>Conclusion: </strong>Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Although immune checkpoint inhibitor treatment for advanced thymic carcinoma exhibits promising efficacy, factors that affect the efficacy and prognosis, including metastases sites, remain uncertain.
Objectives: Our study aimed to investigate the determinants of survival among patients with advanced thymic carcinoma who underwent immunotherapy in real-world settings, with implications for clinical practice.
Designs: Different therapy regimens of immunotherapy were produced to analyze the influence of liver metastases on survival and prognosis for advanced thymic carcinoma patients.
Methods: Data for advanced thymic carcinoma patients receiving immunotherapy and their metastases sites were collected for analysis from seven different hospitals between January 2015 and January 2023. Progression-free survival (PFS) and overall survival (OS) analyses were performed using the Kaplan-Meier method. Cox analysis was used to evaluate factors influencing survival.
Results: The present study analyzed 136 advanced thymic carcinoma patients from seven different hospitals.The PFS for all patients receiving immunotherapy was 6.4 months, while the OS was 24.0 months. The objective response rate was different for patients with liver and non-liver metastases (11.9% versus 37.2%, p = 0.003). The disease control rate values were also different between the two groups (47.6% versus 80.9%, p = 0.037). The PFS for patients with liver metastases demonstrated poor immunotherapy efficacy compared to patients with non-liver metastases (3.0 versus 8.0 months, p < 0.0001). The OS was also significantly different between these two patient groups (16.1 versus 29.1 months, p = 0.009).
Conclusion: Immunotherapy had poor efficacy in advanced thymic carcinoma patients with liver metastases.
{"title":"Poor efficacy of immune checkpoint inhibitor treatment in advanced thymic carcinoma patients with liver metastases.","authors":"Yue Hao, Manyi Xu, Xiaohong Zeng, Yina Wang, Wenxian Wang, Gen Lin, Bihui Li, Jianhui Huang, Chunwei Xu, Yongchang Zhang, Zhengbo Song","doi":"10.1177/17588359241253127","DOIUrl":"10.1177/17588359241253127","url":null,"abstract":"<p><strong>Background: </strong>Although immune checkpoint inhibitor treatment for advanced thymic carcinoma exhibits promising efficacy, factors that affect the efficacy and prognosis, including metastases sites, remain uncertain.</p><p><strong>Objectives: </strong>Our study aimed to investigate the determinants of survival among patients with advanced thymic carcinoma who underwent immunotherapy in real-world settings, with implications for clinical practice.</p><p><strong>Designs: </strong>Different therapy regimens of immunotherapy were produced to analyze the influence of liver metastases on survival and prognosis for advanced thymic carcinoma patients.</p><p><strong>Methods: </strong>Data for advanced thymic carcinoma patients receiving immunotherapy and their metastases sites were collected for analysis from seven different hospitals between January 2015 and January 2023. Progression-free survival (PFS) and overall survival (OS) analyses were performed using the Kaplan-Meier method. Cox analysis was used to evaluate factors influencing survival.</p><p><strong>Results: </strong>The present study analyzed 136 advanced thymic carcinoma patients from seven different hospitals.The PFS for all patients receiving immunotherapy was 6.4 months, while the OS was 24.0 months. The objective response rate was different for patients with liver and non-liver metastases (11.9% <i>versus</i> 37.2%, <i>p</i> = 0.003). The disease control rate values were also different between the two groups (47.6% <i>versus</i> 80.9%, <i>p</i> = 0.037). The PFS for patients with liver metastases demonstrated poor immunotherapy efficacy compared to patients with non-liver metastases (3.0 <i>versus</i> 8.0 months, <i>p</i> < 0.0001). The OS was also significantly different between these two patient groups (16.1 <i>versus</i> 29.1 months, <i>p</i> = 0.009).</p><p><strong>Conclusion: </strong>Immunotherapy had poor efficacy in advanced thymic carcinoma patients with liver metastases.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited.
Objective: We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology.
Design: This study type is a systematic review.
Data sources and methods: This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661).
Results: A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%.
Conclusion: From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure-response relationships and population pharmacokinetics models.
{"title":"Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review.","authors":"Xinya Li, Zaiwei Song, Zhanmiao Yi, Jiguang Qin, Dan Jiang, Zhitong Wang, Huibo Li, Rongsheng Zhao","doi":"10.1177/17588359241250130","DOIUrl":"10.1177/17588359241250130","url":null,"abstract":"<p><strong>Background: </strong>Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited.</p><p><strong>Objective: </strong>We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology.</p><p><strong>Design: </strong>This study type is a systematic review.</p><p><strong>Data sources and methods: </strong>This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661).</p><p><strong>Results: </strong>A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%.</p><p><strong>Conclusion: </strong>From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure-response relationships and population pharmacokinetics models.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Triple-negative breast cancer (TNBC) includes approximately 20% of all breast cancer and is characterized by its aggressive nature, high recurrence rates, and visceral metastasis. Pathological complete response (pCR) is an established surrogate endpoint for survival. The window of opportunity studies provide valuable information on the disease biology prior to definitive treatment.
Objectives: To study the association of dynamic change in pathological, imagining, and genomic biomarkers that can prognosticate pCR. The study aims to develop a composite prognostic score.
Design: Clinical, interventional, and prognostic biomarker study using the novel window of opportunity design.
Methods: The study aims to enroll 80 treatment-naïve, pathologically confirmed TNBC patients, administering a single dose of paclitaxel and carboplatin during the window period before neoadjuvant chemotherapy (NACT). Tumor tissue will be obtained through a tru-cut biopsy, and positron emission tomography and computed tomography scans will be performed for each patient at two time points aiming to evaluate biomarker alterations. This will be followed by the administration of standard dose-dense NACT containing anthracyclines and taxanes, with the study culminating in surgery to assess pCR.
Results: The study would develop a composite prognostic risk score derived from the dynamic change in the Ki-67, tumor-infiltrating lymphocytes, Standardized Uptake Value (SUV max), Standardized Uptake Value for lean body mass (SUL max), and gene expression level pre- and post-intervention during the window period prior to the start of definitive treatment. This outcome will aid in categorizing the disease biology into risk categories.
Trial registration: The current study is approved by the Institutional Ethics Committee [Ethics: Protocol. no. JIP/IEC/2020/019]. This study was registered with ClinicalTrials.gov [CTRI Registration: CTRI/2022/06/043109].
Conclusion: The validated biomarker score will help to personalize NACT protocols in patients in TNBC planned for definitive treatment.
{"title":"Assessment of novel prognostic biomarkers to predict pathological complete response in patients with non-metastatic triple-negative breast cancer using a window of opportunity design.","authors":"Chitradurga Rajashekhar Akshatha, Dhanapathi Halanaik, Rajesh Nachiappa Ganesh, Nanda Kishore, Prasanth Ganesan, Smita Kayal, Harichandra Kumar, Biswajit Dubashi","doi":"10.1177/17588359241248329","DOIUrl":"10.1177/17588359241248329","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) includes approximately 20% of all breast cancer and is characterized by its aggressive nature, high recurrence rates, and visceral metastasis. Pathological complete response (pCR) is an established surrogate endpoint for survival. The window of opportunity studies provide valuable information on the disease biology prior to definitive treatment.</p><p><strong>Objectives: </strong>To study the association of dynamic change in pathological, imagining, and genomic biomarkers that can prognosticate pCR. The study aims to develop a composite prognostic score.</p><p><strong>Design: </strong>Clinical, interventional, and prognostic biomarker study using the novel window of opportunity design.</p><p><strong>Methods: </strong>The study aims to enroll 80 treatment-naïve, pathologically confirmed TNBC patients, administering a single dose of paclitaxel and carboplatin during the window period before neoadjuvant chemotherapy (NACT). Tumor tissue will be obtained through a tru-cut biopsy, and positron emission tomography and computed tomography scans will be performed for each patient at two time points aiming to evaluate biomarker alterations. This will be followed by the administration of standard dose-dense NACT containing anthracyclines and taxanes, with the study culminating in surgery to assess pCR.</p><p><strong>Results: </strong>The study would develop a composite prognostic risk score derived from the dynamic change in the Ki-67, tumor-infiltrating lymphocytes, Standardized Uptake Value (SUV max), Standardized Uptake Value for lean body mass (SUL max), and gene expression level pre- and post-intervention during the window period prior to the start of definitive treatment. This outcome will aid in categorizing the disease biology into risk categories.</p><p><strong>Trial registration: </strong>The current study is approved by the Institutional Ethics Committee [Ethics: Protocol. no. JIP/IEC/2020/019]. This study was registered with ClinicalTrials.gov [CTRI Registration: CTRI/2022/06/043109].</p><p><strong>Conclusion: </strong>The validated biomarker score will help to personalize NACT protocols in patients in TNBC planned for definitive treatment.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11127577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20eCollection Date: 2024-01-01DOI: 10.1177/17588359241254218
Moonki Hong, Sang Wook Lee, Byoung Chul Cho, Min Hee Hong, Sun Min Lim, Nak-Jung Kwon
Background: Programmed death-ligand (PD-L1) expression serves as a predictive biomarker for immune checkpoint inhibitor (ICI) sensitivity in non-small cell lung cancer (NSCLC). Nevertheless, the development of biomarkers that reliably predict ICI response remains an ongoing endeavor due to imperfections in existing methodologies.
Objectives: ICIs have led to a new paradigm in the treatment of NSCLC. The current companion PD-L1 diagnostics are insufficient in predicting ICI response. Therefore, we sought whether the Olink platform could be applied to predict response to ICIs in NSCLC.
Design: We collected blood samples from patients with NSCLC before ICI treatment and retrospectively analyzed proteomes based on their response to ICI.
Methods: Overall, 76 NSCLC patients' samples were analyzed. Proteomic plasma analysis was performed using the Olink platform. Intraplate reproducibility, validation, and statistical analyses using elastic net regression and generalized linear models with clinical parameters were evaluated.
Results: Intraplate coefficient of variation (CV) assays ranged from 3% to 6%, and the interplate CV was 14%. In addition, the Pearson correlation coefficient of the Olink Normalized Protein eXpression data was validated. No statistical differences were observed in the analyses of progressive disease and response to ICIs. Furthermore, no single proteome showed prognostic value in terms of progression-free survival.
Conclusion: In this study, the proximity extension assay-based approach of the Olink panel could not predict the patient's response to ICIs. Our proteomic analysis failed to achieve predictive value in both response or progression to ICIs and progression-free survival (PFS).
{"title":"Multiplex analysis for the identification of plasma protein biomarkers for predicting lung cancer immunotherapy response.","authors":"Moonki Hong, Sang Wook Lee, Byoung Chul Cho, Min Hee Hong, Sun Min Lim, Nak-Jung Kwon","doi":"10.1177/17588359241254218","DOIUrl":"10.1177/17588359241254218","url":null,"abstract":"<p><strong>Background: </strong>Programmed death-ligand (PD-L1) expression serves as a predictive biomarker for immune checkpoint inhibitor (ICI) sensitivity in non-small cell lung cancer (NSCLC). Nevertheless, the development of biomarkers that reliably predict ICI response remains an ongoing endeavor due to imperfections in existing methodologies.</p><p><strong>Objectives: </strong>ICIs have led to a new paradigm in the treatment of NSCLC. The current companion PD-L1 diagnostics are insufficient in predicting ICI response. Therefore, we sought whether the Olink platform could be applied to predict response to ICIs in NSCLC.</p><p><strong>Design: </strong>We collected blood samples from patients with NSCLC before ICI treatment and retrospectively analyzed proteomes based on their response to ICI.</p><p><strong>Methods: </strong>Overall, 76 NSCLC patients' samples were analyzed. Proteomic plasma analysis was performed using the Olink platform. Intraplate reproducibility, validation, and statistical analyses using elastic net regression and generalized linear models with clinical parameters were evaluated.</p><p><strong>Results: </strong>Intraplate coefficient of variation (CV) assays ranged from 3% to 6%, and the interplate CV was 14%. In addition, the Pearson correlation coefficient of the Olink Normalized Protein eXpression data was validated. No statistical differences were observed in the analyses of progressive disease and response to ICIs. Furthermore, no single proteome showed prognostic value in terms of progression-free survival.</p><p><strong>Conclusion: </strong>In this study, the proximity extension assay-based approach of the Olink panel could not predict the patient's response to ICIs. Our proteomic analysis failed to achieve predictive value in both response or progression to ICIs and progression-free survival (PFS).</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-19eCollection Date: 2024-01-01DOI: 10.1177/17588359241253113
Maahum Mehdi, Aniko Szabo, Aditya Shreenivas, James P Thomas, Susan Tsai, Kathleen K Christians, Douglas B Evans, Callisia N Clarke, William A Hall, Beth Erickson, Gulrayz Ahmed, Bicky Thapa, Thomas McFall, Ben George, Razelle Kurzrock, Mandana Kamgar
Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established.
Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients.
Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021.
Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively.
Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.
{"title":"Chemotherapy-free treatment targeting fusions and driver mutations in <i>KRAS</i> wild-type pancreatic ductal adenocarcinoma, a case series.","authors":"Maahum Mehdi, Aniko Szabo, Aditya Shreenivas, James P Thomas, Susan Tsai, Kathleen K Christians, Douglas B Evans, Callisia N Clarke, William A Hall, Beth Erickson, Gulrayz Ahmed, Bicky Thapa, Thomas McFall, Ben George, Razelle Kurzrock, Mandana Kamgar","doi":"10.1177/17588359241253113","DOIUrl":"10.1177/17588359241253113","url":null,"abstract":"<p><strong>Background: </strong><i>KRAS</i> wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established.</p><p><strong>Objectives: </strong>The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with <i>KRAS</i>-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients.</p><p><strong>Design: </strong>We reviewed electronic medical records of patients with <i>KRAS-WT</i> PDAC and advanced disease (<i>n</i> = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021.</p><p><strong>Methods: </strong>Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.</p><p><strong>Results: </strong>Of 236 PDAC patients, 14 had advanced/metastatic disease with <i>KRAS-WT</i> tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with <i>BRAF</i> alterations, two (14%) with fusions [<i>RET-PCM1</i> and <i>FGFR2-POC1B</i> (<i>N</i> = 1 each)]; and one with a druggable <i>EGFR</i> (<i>EGFR</i> E746_A755delISERD) variant; two other patients had an <i>STK11</i> and a <i>MUTYH</i> alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for <i>EGFR</i>-altered tumor, followed by osimertinib/capmatinib when <i>MET</i> amplification emerged (first-line therapy); (ii) pralsetinib for <i>RET</i> fusion (fifth line); and (iii) dabrafenib/trametinib for <i>BRAF</i> N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively.</p><p><strong>Conclusion: </strong>Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic <i>KRAS-WT</i> PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11104030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17eCollection Date: 2024-01-01DOI: 10.1177/17588359241249627
Raza Khan, Niamh Coleman
Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months. There is an undeniable urgent need for better responses, better agents, novel therapeutic approaches, and more rational, biomarker-driven clinical trials in SCLC. In this review, we discuss the rationale and current understanding of the biology of SCLC in the modern era of immunotherapy, discuss recent advances in front-line immunotherapeutic approaches that have changed clinical practice globally, provide an overview of some of the challenges and limitations that have staggered immune checkpoint blockade in SCLC, and explore some of the novel immunotherapeutic approaches currently being investigated.
{"title":"Challenges and opportunities in the immunotherapy era: balancing expectations with hope in small-cell lung cancer.","authors":"Raza Khan, Niamh Coleman","doi":"10.1177/17588359241249627","DOIUrl":"10.1177/17588359241249627","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is a biologically aggressive subtype of lung cancer, a lethal disease characterized by rapid tumor growth, early relapse, a strong tendency for early widespread metastasis, and high genomic instability, making it a formidable foe in modern oncology practice. While the management of non-SCLC has been revolutionized in the era of immunotherapy, progress in SCLC has been more muted. Recent randomized phase III clinical trials have combined programmed death ligand-1 inhibitors to a chemotherapy backbone and demonstrated improved survival; however, the absolute benefit observed is short months. There is an undeniable urgent need for better responses, better agents, novel therapeutic approaches, and more rational, biomarker-driven clinical trials in SCLC. In this review, we discuss the rationale and current understanding of the biology of SCLC in the modern era of immunotherapy, discuss recent advances in front-line immunotherapeutic approaches that have changed clinical practice globally, provide an overview of some of the challenges and limitations that have staggered immune checkpoint blockade in SCLC, and explore some of the novel immunotherapeutic approaches currently being investigated.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11102705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141066680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-13eCollection Date: 2024-01-01DOI: 10.1177/17588359241250158
Mauricio Fernando Ribeiro, Elizabeth G Demicco, Albiruni Ryan Abdul Razak
Intimal sarcoma (InS) is an ultra-rare and aggressive subtype of soft tissue sarcoma (STS). It usually arises in large mediastinal arteries and the heart. In the advanced setting, sequential cytotoxic chemotherapy is often used, mainly based on retrospective studies and case series but with modest benefit. The use of immune checkpoint inhibitors is a promising strategy for some STS, but identifying biomarkers of response remains challenging due to disease rarity and heterogeneity. A reactive and pro-inflammatory tumor microenvironment (TME) is believed to be associated with better outcomes for patients receiving anti-PD-1-based regimens, generating the rationale to explore this strategy in malignancies with this characteristic, such as InS. We report three cases of advanced InS patients experiencing partial response to pembrolizumab-based therapy despite low tumor mutational burden and absence of mismatch-repair deficiency. We hypothesize that TME-related characteristics such as PD-L1 expression and the presence of tertiary lymphoid structures might explain this phenomenon.
内膜肉瘤(InS)是软组织肉瘤(STS)中一种极为罕见的侵袭性亚型。它通常发生在纵隔大动脉和心脏。在晚期,通常采用序贯细胞毒性化疗,主要基于回顾性研究和病例系列,但疗效一般。使用免疫检查点抑制剂是治疗某些 STS 的有希望的策略,但由于疾病的罕见性和异质性,确定反应的生物标志物仍具有挑战性。反应性和促炎性肿瘤微环境(TME)被认为与患者接受基于抗PD-1的治疗方案后获得更好的疗效有关,这为在具有这一特征的恶性肿瘤(如InS)中探索这一策略提供了理论依据。我们报告了三例晚期 InS 患者,尽管他们的肿瘤突变负荷较低且不存在错配修复缺陷,但却对基于 pembrolizumab 的治疗产生了部分反应。我们推测,PD-L1表达和三级淋巴结构的存在等TME相关特征可能解释了这一现象。
{"title":"Clinical activity of pembrolizumab in refractory <i>MDM2</i>-amplified advanced intimal sarcomas.","authors":"Mauricio Fernando Ribeiro, Elizabeth G Demicco, Albiruni Ryan Abdul Razak","doi":"10.1177/17588359241250158","DOIUrl":"10.1177/17588359241250158","url":null,"abstract":"<p><p>Intimal sarcoma (InS) is an ultra-rare and aggressive subtype of soft tissue sarcoma (STS). It usually arises in large mediastinal arteries and the heart. In the advanced setting, sequential cytotoxic chemotherapy is often used, mainly based on retrospective studies and case series but with modest benefit. The use of immune checkpoint inhibitors is a promising strategy for some STS, but identifying biomarkers of response remains challenging due to disease rarity and heterogeneity. A reactive and pro-inflammatory tumor microenvironment (TME) is believed to be associated with better outcomes for patients receiving anti-PD-1-based regimens, generating the rationale to explore this strategy in malignancies with this characteristic, such as InS. We report three cases of advanced InS patients experiencing partial response to pembrolizumab-based therapy despite low tumor mutational burden and absence of mismatch-repair deficiency. We hypothesize that TME-related characteristics such as PD-L1 expression and the presence of tertiary lymphoid structures might explain this phenomenon.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-11eCollection Date: 2024-01-01DOI: 10.1177/17588359241248352
Yanhua Wang, Manyi Xu, Ke Wang, Yue Hao, Chunwei Xu, Zhengbo Song
Background: While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal-epithelial transition (MET) alterations in the real world.
Objectives: We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance.
Design: Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations.
Methods: We conducted analyses on the efficacy and safety of mesenchymal-epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan-Meier method.
Results: Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation (n = 50), MET primary amplification (amp) (n = 25), and secondary amp (n = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 versus 6.6 versus 4.5 months, p = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher.
Conclusion: MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.
{"title":"Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations.","authors":"Yanhua Wang, Manyi Xu, Ke Wang, Yue Hao, Chunwei Xu, Zhengbo Song","doi":"10.1177/17588359241248352","DOIUrl":"10.1177/17588359241248352","url":null,"abstract":"<p><strong>Background: </strong>While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal-epithelial transition (MET) alterations in the real world.</p><p><strong>Objectives: </strong>We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance.</p><p><strong>Design: </strong>Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations.</p><p><strong>Methods: </strong>We conducted analyses on the efficacy and safety of mesenchymal-epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan-Meier method.</p><p><strong>Results: </strong>Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation (<i>n</i> = 50), MET primary amplification (amp) (<i>n</i> = 25), and secondary amp (<i>n</i> = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 <i>versus</i> 6.6 <i>versus</i> 4.5 months, <i>p</i> = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher.</p><p><strong>Conclusion: </strong>MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}